An FDA advisory committee panel voted against recommending premarket approval for PneumRx’s Elevair lung implant for patients with severe emphysema.
The novel device is designed to reduce hyperinflated volume and improve function using a series of coils that gather and contract the tissue from inside the lung. Reducing resting lung volume allows patients to take in more air with each breath, the company said, and lessens stress on the chest from heavy breathing.
However, in an 8-3 vote June 14 indicating the device's benefits did not outweigh the risks, members of the agency’s anesthesiology and respiratory devices panel sided with safety concerns noted by FDA reviewers. In addition, the panel voted 7-5 in favor of the device’s safety, but 5-7 that they believed it was effective.
Although PneumRx’s clinical trial eventually demonstrated statistically significant improvement in a six-minute walking test, a 2015 protocol amendment had altered the study’s analysis methods before database lock and unblinding.
The original model, proposing a parametric analysis of covariance comparing the means between the two study arms, did not demonstrate statistically significant results. However, the later, non-parametric model—this time comparing the medians—did.
The study also measured the amount of air a patient could exhale within one second, and changes in scores in a patient-reported quality-of-life questionnaire. In their briefing memo (PDF) to the advisory panel, agency staff said they were uncertain of the all three endpoints’ clinical meaningfulness, especially when the study lacked a blinded sham arm.
In addition, reviewers flagged how the observed treatment effect across all endpoints was consistently lower in U.S. patients compared to those outside the country, urging caution when considering the pooled data.
The company’s 12-month, prospective, assessor-blinded study randomized 315 subjects in the U.S., Canada and Europe, with four years of follow-up. Patients in the control arm were followed for 12 months, then given the option to enroll and receive the implant in a single-arm crossover study. Participants and investigators were not blinded, and both arms were treated with the standard-of-care.
RELATED: Britain's BTG scoops up pulmonology outfit PneumRx for up to $475M
After one year, patients receiving the implant could walk a median difference of 14.6 meters farther in six minutes compared to the control arm, while the adjusted mean difference only totaled 10.2 meters.
According to the FDA, major complications including COPD exacerbation and lower respiratory tract infections were increased in the treatment arm of the study in the first 12 months following the procedure, with similar risks seen in the crossover population. One hundred percent of treated subjects and 88.5% of controls reported at least one adverse event throughout the 12 months, the company said.
The study saw a total of 18 deaths within the 12-month follow-up period, including 10 of 155 in the coil treatment group and eight of 157 subjects in the control. Seven out of the 10 deaths in the treatment group were assessed to be possibly or probably related to the device or insertion procedure, where the coil is delivered via a bronchoscope, with one autopsy report showing what the FDA described as “extensive fibrosis” at the implant site.
The device previously received a CE Mark in Europe for late-stage emphysema in October 2010. In its briefing (PDF) for the panel, PneumRx cited about seven years’ worth of commercialization experience outside the U.S., including detailed labeling and a physician training program to inform users of the Elevair system’s risks and benefits.